ABSTRACT
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with a high recurrence and mortality rate. In this study, a series of ß-cyclocitral-derived mono-carbonyl curcumin analogs were synthesized and their anticancer properties were evaluated. Among the series, A19 exhibited the strongest cytotoxic activity by inhibiting cell viability and colony formation, inducing cell cycle G2/M phase arrest and cell apoptosis of HCC HepG2 and Huh-7 cells, while having almost no cytotoxicity on normal liver MIHA cells. Mechanistically, our results demonstrated that A19 triggered intense DNA damage via suppression of the ERK/JNK/p38 MAPK signaling pathway. Additionally, a combination of A19 with sorafenib significantly induced synergistic cytotoxicity in HCC cells. Overall, our results indicate the potential of A19 as a novel chemotherapeutic drug administered either separately or in combined therapy for HCC treatment.
Subject(s)
Antineoplastic Agents , Carcinoma, Hepatocellular , Curcumin , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/pathology , Curcumin/pharmacology , Curcumin/therapeutic use , Hep G2 Cells , Signal Transduction , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Apoptosis , Cell Proliferation , Cell Line, TumorABSTRACT
There remains a critical need for more effective therapies for the treatment of castration-resistant prostate cancer (CRPC), which is the leading cause of death in patients with prostate cancer. In this study, a series of sanjuanolide derivatives were designed, synthesized and evaluated as potential anti-CRPC agents. Most of the compounds had excellent selectivity for CRPC cells with IC50 values < 20 µM. Moreover, minimal side effects on human normal hepatic MIHA cells and normal prostatic stromal myofibroblast WPMY-1 cells were observed, with IC50 > 100 µM. The representative compound S07 slowed down the proliferative rate of CRPC cells, promoted cell apoptosis and caused G2/M phase accumulation, as well as G1/G0 phase reduction. Further mechanistic studies showed that S07 treatment triggered intense DNA damage and provoked strong DNA damage response in a dose-dependent manner. These findings suggested that sanjuanolide derivatives, especially S07, selectively induced CRPC cell death by triggering intense DNA damage and DNA damage response.